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Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms

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Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms

dc.contributor.author	Sofat, Reecha
dc.contributor.author	Hingorani, Aroon D.
dc.contributor.author	Smeeth, Liam
dc.contributor.author	Humphries, Steve E.
dc.contributor.author	Talmud, Philippa J.
dc.contributor.author	Cooper, Jackie
dc.contributor.author	Shah, Tina
dc.contributor.author	Sandhu, Manjinder S.
dc.contributor.author	Ricketts, Sally L.
dc.contributor.author	Boekholdt, S. Matthijs
dc.contributor.author	Wareham, Nicholas
dc.contributor.author	Khaw, Kay Tee
dc.contributor.author	Kumari, Meena
dc.contributor.author	Kivimaki, Mika
dc.contributor.author	Marmot, Michael
dc.contributor.author	Asselbergs, Folkert W.
dc.contributor.author	van der Harst, Pim
dc.contributor.author	Dullaart, Robin P.F.
dc.contributor.author	Navis, Gerjan
dc.contributor.author	van Veldhuisen, Dirk J.
dc.contributor.author	Van Gilst, Wiek H.
dc.contributor.author	Thompson, John F.
dc.contributor.author	McCaskie, Pamela
dc.contributor.author	Palmer, Lyle J.
dc.contributor.author	Arca, Marcello
dc.contributor.author	Quagliarini, Fabiana
dc.contributor.author	Gaudio, Carlo
dc.contributor.author	Cambien, François
dc.contributor.author	Nicaud, Viviane
dc.contributor.author	Poirer, Odette
dc.contributor.author	Gudnason, Vilmundur
dc.contributor.author	Isaacs, Aaron
dc.contributor.author	Witteman, Jacqueline C.M.
dc.contributor.author	van Duijn, Cornelia M.
dc.contributor.author	Pencina, Michael
dc.contributor.author	Vasan, Ramachandran S.
dc.contributor.author	D'Agostino, Ralph B.
dc.contributor.author	Ordovas, Jose M.
dc.contributor.author	Li, Tricia Y.
dc.contributor.author	Kakko, Sakari
dc.contributor.author	Kauma, Heikki
dc.contributor.author	Savolainen, Markku J.
dc.contributor.author	Kesäniemi, Antero
dc.contributor.author	Sandhofer, Anton
dc.contributor.author	Paulweber, Bernhard
dc.contributor.author	Sorlí Guerola, José Vicente
dc.contributor.author	Goto, Akimoto
dc.contributor.author	Yokoyama, Shinji
dc.contributor.author	Okumura, Kenji
dc.contributor.author	Horne, Benjamin D.
dc.contributor.author	Packard, Chris
dc.contributor.author	Freeman, Dilys
dc.contributor.author	Ford, Ian
dc.contributor.author	Sattar, Naveed
dc.contributor.author	McCormack, Valerie
dc.contributor.author	Lawlor, Debbie A.
dc.contributor.author	Ebrahim, Shah
dc.contributor.author	Smith, George Davey
dc.contributor.author	Kastelein, John J.P.
dc.contributor.author	Deanfield, John
dc.contributor.author	Casas, Juan P.
dc.date.accessioned	2011-06-02T09:27:56Z
dc.date.available	2011-06-02T09:27:56Z
dc.date.issued	2010
dc.identifier.citation	SOFAT, Reecha ; Hingorani, Aroon D. ; Smeeth, Liam ; Humphries, Steve E. ; Talmud, Philippa J. ; Cooper, Jackie ; Shah, Tina ; Sandhu, Manjinder S. ; Ricketts, Sally L. ; Boekholdt, S. Matthijs ; Wareham, Nicholas ; Khaw Kay, Tee ; Kumari, Meena ; Kivimaki, Mika ; Marmot, Michael ; Asselbergs, Folkert W. ; Van der Harst, Pim ; Dullaart, Robin P.F. ; Navis, Gerjanvan ; Veldhuisen, Dirk J. ; Van Gilst, Wiek H. ; Thompson, John F. ; McCaskie, Pamela ; Palmer, Lyle J. ; Arca, Marcello ; Quagliarini, Fabiana ; Gaudio, Carlo ; Cambien, François ; Nicaud, Viviane ; Poirer, Odette ; Gudnason, Vilmundur ; Isaacs, Aaron ; Witteman, Jacqueline C.M. ; van Duijn, Cornelia M. , Pencina, Michael ; Vasan, Ramachandran S. ; D'Agostino, Ralph B. ; Ordovas, Jose ; Li, Tricia Y. ; Kakko, Sakari ; Kauma, Heikki ; Savolainen, Markku J. ; Kesäniemi, Antero ; Sandhofer, Anton ; Paulweber, Bernhard ; Sorli Guerola, Jose Vicente ; Goto, Akimoto ; Yokoyama, Shinji ; Okumura, Kenji ; Horne, Benjamin D. ; Packard, Chris ; Freeman, Dilys ; Ford, Ian ; Sattar, Naveed ; McCormack, Valerie ; Lawlor, Debbie A. ; Ebrahim, Shah ; Smith, George Davey ; Kastelein, John J.P. ; Deanfield, John ; Casas, Juan P., 2010, Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms, Circulation, vol. 121, no. 1, p. 52-62	en
dc.identifier.uri	http://hdl.handle.net/10550/18830
dc.description.abstract	Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI –0.28 to 0.60 mm Hg) and diastolic blood pressure (–0.04 mm Hg, 95% CI –0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.	en
dc.language.iso	en	en
dc.subject	Genetics ; Pharmacology ; Epidemiology ; High-density lipoproteins	en
dc.title	Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms	en
dc.type	journal article	es_ES
dc.subject.unesco	UNESCO::CIENCIAS MÉDICAS	en
dc.subject.unesco	UNESCO::CIENCIAS MÉDICAS ::Medicina interna	en
dc.identifier.doi	10.1161/CIRCULATIONAHA.109.865444	en
dc.identifier.idgrec	055068	en
dc.type.hasVersion	VoR	es_ES
dc.identifier.url	http://circ.ahajournals.org/cgi/reprint/121/1/52	en